The present invention relates generally to a method for preserving and/or restoring functionality in muscle tissue subject to ischemia, particularly tissue such as the myocardium subject to reperfusion.
It has been reported by Turner and Walker in J. Biological Chem., Vol. 262, p. 6605-9 (1989) that the dietary ingestion of the creatine analogue cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) imparts to tissue the ability to sustain high levels of myocardial adenosine triphosphate (ATP) or at least to delay the depletion of ATP during total ischemia. The cyclocreatine is reported to be effective provided the dietary supplement is ingested over a period of at least two days prior to the onset of ischemia but achieves a maximum response where the dietary supplement has been provided over a period of about ten to fourteen days prior to onset of ischemia. It is believed this period of time is required in order to permit the dietary supplement, cyclocreatine, to undergo phosphorylation since it is the synthetic phosphagen that is believed to be effective in helping to conserve the total adenylate pool and to buffer the decrease in the ratio of ATP to free adenosine diphosphate (ADP).
Jacobstein et al in J. Am. Coll. Cardial, Vol. 14, p. 246-251 (July 1989) have confirmed that the dietary ingestion of cyclocreatine preserves myocardial ATP during ischemia and also have established that cyclocreatine ingestion delays the development of acidosis and the onset of poor ventricular compliance, as evidenced by a rigor-like increase in tonic pressure, during ischemia. However, it is known that substantial cell damage also can occur during post-ischemic reperfusion and the effect of cyclocreatine on restoring tissue function in an intact muscle tissue model following reperfusion is not known.
Accordingly an object of the present invention is to provide a system for effecting the prompt recovery of tissue function, such as contractility, in muscle tissue during and following post-ischemic reperfusion. Included in this object is the provision for the administration of a creatine analogue such as cyclocreatine to restore contractility function during perfusion in ischemic muscle tissue, particularly to restore and sustain myocardial contractility function in patients with coronary insufficiency. Such a system offers potential for allowing better clinical management of patients with both controlled and uncontrolled ischemic conditions. In the controlled category are those patients with angina or undergoing heart surgery, organ transplant or similar procedures. In the uncontrolled category are those patients that have already experienced myocardial infarct attack. It is believed this treatment also may increase exercise tolerance in patients with known coronary artery disease and increase aortic clamp time tolerance during cardiac surgery. Thus, the treatment can be used as a presurgical procedure or, following a myocardial infarct attack, as a preventative measure to avoid damage otherwise caused by reperfusion and minimize continued ischemic damage after a myocardial infarct.
Other objects and advantages will be in part obvious and in part pointed out more in detail hereinafter.
These and related objects are achieved in accordance with the present invention by providing a method of achieving prompt recovery of functionality in muscle tissue comprising the step of administering, preferably by injection or infusion, an effective amount of cyclocreatine prior to the onset of ischemia, or after myocardial infarct, for restoring and preserving muscle tissue functionality post-ischemia.
A better understanding of the invention will be obtained from the following detailed description and the accompanying drawing as well as from the illustrative applications of the invention, including the process steps and components thereof and the relationship of one or more of such steps or components with respect to each of the others, as well as the features, characteristics, compositions, properties and relation of elements described and exemplified herein.